Control of autophagic cell death by caspase-10 in multiple myeloma

Laurence Lamy, Vu N. Ngo, N. C.Tolga Emre, Arthur L. Shaffer, Yandan Yang, Erming Tian, Vinod Nair, Michael J. Kruhlak, Adriana Zingone, Ola Landgren, Louis M. Staudt

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

We performed a loss-of-function RNA interference screen to define therapeutic targets in multiple myeloma, a genetically diverse plasma cell malignancy. Unexpectedly, we discovered that all myeloma lines require caspase-10 for survival irrespective of their genetic abnormalities. The transcription factor IRF4 induces both caspase-10 and its associated protein cFLIPL in myeloma, generating a protease that does not induce apoptosis but rather blocks an autophagy-dependent cell death pathway. Caspase-10 inhibits autophagy by cleaving the BCL2-interacting protein BCLAF1, itself a strong inducer of autophagy that acts by displacing beclin-1 from BCL2. While myeloma cells require a basal level of autophagy for survival, caspase-10 tempers this response to avoid cell death. Drugs that disrupt this vital balance may have therapeutic potential in myeloma.

Original languageEnglish (US)
Pages (from-to)435-449
Number of pages15
JournalCancer Cell
Volume23
Issue number4
DOIs
StatePublished - Apr 15 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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